Antibiotic potentiation and inhibition of cross-resistance in pathogens associated with cystic fibrosis

Critical Gram-negative pathogens, likePseudomonas,StenotrophomonasandBurkholderia, have become resistant to most antibiotics. Complex resistance profiles together with synergistic interactions between these organisms increase the likelihood of treatment failure in distinct infection settings, for example in the lungs of cystic fibrosis patients. Here, we discover that cell envelope protein homeostasis pathways underpin both antibiotic resistance and cross-protection in CF-associated bacteria. We find that inhibition of oxidative protein folding inactivates multiple species-specific resistance proteins. Using this strategy, we sensitize multi-drug resistantPseudomonas aeruginosato β-lactam antibiotics and demonstrate promise of new treatment avenues for the recalcitrant pathogenStenotrophomonas maltophilia. The same approach also inhibits cross-protection between resistantS. maltophiliaand susceptibleP. aeruginosa, allowing eradication of both commonly co-occurring CF-associated organisms. Our results provide the basis for the development of next-generation strategies that target antibiotic resistance, while also impairing specific interbacterial interactions that enhance the severity of polymicrobial infections.